Mol Brain [JOURNAL]
Sun
200 papers
Comprehensive protein synthesis inhibition impairs natural and artificial memory recall.
Kim Y, Hong I, Kaang BK
Mol Brain · 2026 Apr · PMID 42057075 · Full text
Protein synthesis is critical for long-lasting memory formation and synaptic plasticity. However, whether protein synthesis is required for artificially evoked memory retrieval remains debated. To address this, we used a...
Protein synthesis is critical for long-lasting memory formation and synaptic plasticity. However, whether protein synthesis is required for artificially evoked memory retrieval remains debated. To address this, we used a translation-inhibitor cocktail (CKT; anisomycin and cycloheximide) to achieve a more comprehensive blockade of protein synthesis compared to more commonly used anisomycin alone (ANI). When administered immediately after memory acquisition, ANI impaired natural recall while still showing preserved artificial recall. In contrast, CKT treatment showed significant impairment in both natural and artificial recall. Together, these results provide additional evidence that de novo protein synthesis is required for both natural and artificial memory recall.
Impaired phrenic nerve axon development and diaphragm neuromuscular junction formation in embryonic Cyfip2-null mice.
Kim SY, Oh JY, Kim US … +3 more , Ma R, Kim Y, Han K
Mol Brain · 2026 Apr · PMID 42035098 · Full text
Pathogenic variants in CYFIP2 cause developmental and epileptic encephalopathy 65 (DEE65) and have been predominantly investigated in the context of central nervous system dysfunction. However, emerging clinical evidence...
Pathogenic variants in CYFIP2 cause developmental and epileptic encephalopathy 65 (DEE65) and have been predominantly investigated in the context of central nervous system dysfunction. However, emerging clinical evidence suggests that peripheral nervous system (PNS) involvement may also contribute to disease manifestations. To explore this possibility, we examined the role of CYFIP2 in the development of the phrenic neuromuscular system, which is essential for neonatal respiration. Because conventional Cyfip2-null (Cyfip2) mice exhibit perinatal lethality, we analyzed phrenic nerve axon development and diaphragm neuromuscular junction (NMJ) formation in embryonic mice. At embryonic day 16.5, Cyfip2 embryos displayed significantly reduced phrenic nerve axon length and branching compared to wild-type controls. Postsynaptic acetylcholine receptor (AChR) clustering in Cyfip2 diaphragms showed spatial heterogeneity: sparse regions exhibited a significant increase in endplate bandwidth, whereas dense regions showed a decreasing trend. Further analysis using synaptophysin and α-bungarotoxin labeling revealed reduced pre- and post-synaptic puncta density and decreased colocalization, despite preserved puncta intensity and volume, indicating impaired synaptic organization. Together, these findings demonstrate that CYFIP2 is required for proper phrenic nerve innervation and NMJ organization during embryonic development. This study extends the functional scope of CYFIP2 to the PNS and establishes the diaphragm as a tractable model for investigating peripheral mechanisms underlying CYFIP2-associated neurodevelopmental disorders.
Genome-wide mapping of stress-responsive lncRNA, uc.104, reveals the chromatin-mediated regulation of stress and plasticity-related genes in the hippocampus of chronic restraint rats.
Verma AK, Roy B, Prall K … +2 more , Hulwi E, Dwivedi Y
Mol Brain · 2026 Apr · PMID 42002767 · Full text
Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recog...
Chronic stress significantly impacts hippocampal function through transcriptional and epigenetic mechanisms. While the roles of lncRNAs in stress-related transcriptional and epigenetic regulation have recently been recognized, their genome-wide functions controlling the transcriptional network remain largely unclear. Evidence indicates that the lncRNA uc.104 is involved in stress responses; however, its genome-wide chromatin interactions and gene regulatory effects are yet to be explored. To examine this, we combined chromatin isolation by RNA purification sequencing (ChIRP-seq) and RNA sequencing (RNA-seq) in the hippocampus from handled control and chronic restraint stress (CRS) rats. ChIRP-seq identified 6,664 uc.104 binding peaks under CRS, including 6,517 enriched and 149 reduced. Many peaks were mapped to intronic and promoter-proximal regions of protein-coding genes. Integration of ChIRP-seq with RNA-seq data revealed 1,839 differentially expressed genes associated with uc.104 binding sites, with 106 high-confidence overlaps. Several genes (Gabra3, Htr7, Irs1, Gpr37, Clu, Hspa1b, Ppp3r2, Nfasc, Pcdhac2, and Cysltr2) identified as regulatory targets of uc.104, have been directly implicated in stress responses, synaptic plasticity, and neuroinflammation. Gene ontology and Synapse GO (SynGO) analyses revealed significant enrichment for processes involving dendritic spine formation, synapse organization, and pre- and postsynaptic signaling. Protein-protein interaction analysis identified hub genes, including EGFR, CDC42, IGF1R, CTNNB1, CALM1, CALM3, POLR2A, MDM2, TBP, and CSNK1E, several of which have been linked to stress-responsive pathways. Together, our findings reveal that uc.104 binding to chromatin near stress- and synapse-related genes may act as a regulator of stress-responsive transcriptional networks in the hippocampus. By linking uc.104 occupancy to stress and synaptic responsive genes, this study highlights uc.104 as a potential mediator of stress-induced hippocampal malfunctions.
Thalamic homeostatic transcriptomic signatures are altered in a mouse model of cholestatic liver injury and are mitigated by systemic TNF neutralization.
Almishri W, Dunn JF, Swain MG
Mol Brain · 2026 Apr · PMID 41998777 · Full text
Cholestatic liver diseases (CLD), including PBC and PSC, are frequently associated with debilitating sickness‑behavior symptoms such as fatigue, cognitive impairment, and anxiety/depression, which have poorly defined eti...
Cholestatic liver diseases (CLD), including PBC and PSC, are frequently associated with debilitating sickness‑behavior symptoms such as fatigue, cognitive impairment, and anxiety/depression, which have poorly defined etiology and limited treatment options, substantially reducing quality of life. Across immune‑mediated diseases, thalamic changes have been well documented and found to correlate with a number of theses symptoms. Changes in thalamic structure and neural connectivity have been previously identified in PBC patients by us and other groups. These changes include findings indicating reduced tissue neuronal density and myelination, decreased thalamic size, and changes in functional neural connectivity between the thalamus and basal ganglia and cortical behavior-regulating areas that correlated with symptom severity. These observations implicate altered thalamic structure and function in the genesis of CLD-related sickness‑behavior symptoms. Therefore, we used a well characterized mouse model of CLD due to bile duct ligation (BDL) to mechanistically examine how CLD impacts thalamic structure and function. BDL mice showed reduced thalamic volume compared to sham-ligated controls, as determined by MRI, and an altered thalamic RNA-seq transcriptomic signature with predicted molecular activity consistent with inhibition of cellular growth, proliferation, neurite formation, neural function, and myelination, as well as enhanced apoptosis. Additionally, BDL was associated with changes in gene expression for key thalamic nervous system signaling pathways that regulate neurotransmission and behavior. We have previously demonstrated that systemic TNF is a key regulator of liver-to-brain communication and the development of adverse behavioral symptoms in BDL mice. Therefore, we administered anti-TNF antibody to neutralize systemic TNF in BDL mice and determined the impact on thalamic transcriptomic changes. TNF neutralization attenuated BDL-associated thalamic transcriptomic changes and enhanced gene expression in pathways regulating neurotransmission, cell proliferation, and those associated with neuron survival, although myelination pathways remained unaltered. We show that reduced thalamic volume in BDL mice is associated with transcriptomic alterations suggesting inhibition of structural machinery and dysfunction of neural signaling; findings that are significantly attenuated after systemic TNF neutralization. Our findings suggest that TNF inhibition may represent a potential novel approach to attenuate thalamic changes in CLD.
Altered ECM deposition and cell adhesion signaling in a human cortical organoid model of fragile X syndrome.
Havusha-Laufer S, Krishnaswamy VR, Krugliak-Shechter N … +7 more , Shenoy A, Karlinski Zur M, Kuznitsov-Yanovsky L, Solomonov I, Hanna JH, Sagi I, Ben Yosef D
Mol Brain · 2026 Apr · PMID 41987282 · Full text
Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the l...
Fragile X Syndrome (FXS) is the most common inherited intellectual disability, and the most common monogenic cause of autism spectrum disorder (ASD). It is caused by epigenetic silencing of the FMR1 gene leading to the loss of FMRP, an RNA-binding protein that regulates local mRNA translation in neuronal dendrites, crucial for synapse development. Three-dimensional (3D) brain organoid models derived through in vitro differentiation of pluripotent stem cells offer a powerful tool to dissect the underlying mechanisms of neurodevelopmental disorders. Here, we generated human FXS and control organoids using isogenic human embryonic stem cell clones with and without the FXS mutation. Our results show that mature FXS cortical brain organoids can be derived by inhibiting the TGFβ and Wnt pathways. Moreover, expression analyses including immunofluorescence, qRT-PCR, proteomics and western blotting reveal altered levels of neuronal markers and ECM deposition along with modulated downstream signaling molecules. Interestingly, in silico analysis of proteomics revealed several altered pathways, such as cell adhesion, regulation of neurogenesis and cell cycle that are implicated in FXS. Collectively, our unique FXS-organoids derived from isogenic hESC lines may serve as a model for studying the pathology of FXS disorder and for developing therapeutical intervention.
FCHO1 fine-tunes synaptic vesicle endocytosis in an activity-dependent manner.
Lee HJ, Lee W, Kim SH
Mol Brain · 2026 Apr · PMID 41943152 · Full text
Synaptic vesicle (SV) recycling is critical for sustaining neurotransmission. Although FCHO1, a protein containing both an F-BAR domain and a μ-homology (μ-HD) domain, is recognized as a nucleator of clathrin-mediated en...
Synaptic vesicle (SV) recycling is critical for sustaining neurotransmission. Although FCHO1, a protein containing both an F-BAR domain and a μ-homology (μ-HD) domain, is recognized as a nucleator of clathrin-mediated endocytosis in non-neuronal systems, its physiological role at synapses remains unclear. Here, we investigated the function of FCHO1 in SV endocytosis at central synapses using a combination of shRNA-mediated knockdown and pHluorin-based live imaging. Within defined stimulation paradigms (25-300 action potentials at 10 Hz), depletion of FCHO1 markedly slowed endocytic kinetics across all stimulation intensities and was fully rescued by re-expression of an shRNA-resistant construct. Domain-specific functional analyses revealed stimulation-strength-dependent functional requirements. The F-BAR domain was sufficient to support vesicle retrieval under low stimulation conditions, whereas the μ-homology domain (μ-HD) became essential as stimulation strength increased. These findings support a model in which FCHO1 operates as a demand-sensitive scaffold within the endocytic pathway, with distinct structural domains differentially required as neural activity and consequently endocytic load escalates. Our results establish FCHO1 as a critical regulator of SV endocytosis and suggest that multidomain endocytic proteins may scale their functional contributions according to the magnitude of neuronal activation.
Hippocampal transcriptome profiling in a 22q11.2 deletion syndrome mouse model: comparison with human schizophrenia.
Yonemaru H, Ozawa T, Hikida T
Mol Brain · 2026 Apr · PMID 41937202 · Full text
22q11.2 deletion syndrome (22q11.2DS) confers one of the highest genetic risks for schizophrenia, yet the molecular mechanisms remain incompletely understood. We performed comprehensive RNA sequencing of the dorsal hippo...
22q11.2 deletion syndrome (22q11.2DS) confers one of the highest genetic risks for schizophrenia, yet the molecular mechanisms remain incompletely understood. We performed comprehensive RNA sequencing of the dorsal hippocampus in Df1/+ mice, a 22q11.2DS model, integrating behavioral assessment and cross-species comparison with human schizophrenia postmortem data. Df1/+ mice exhibited selective contextual fear memory impairment without gross locomotor deficits. Transcriptomic analysis using integrated over-representation and gene set enrichment approaches revealed upregulation of synaptic signaling pathways, including glutamatergic and GABAergic neurotransmission, alongside downregulation of translational machinery and ribosomal proteins. Top upregulated pathways included "regulation of postsynaptic membrane potential" and "postsynapse organization," featuring glutamatergic receptors, voltage-gated channels, and synaptic adhesion molecules. Downregulated pathways centered on protein synthesis, including cytoplasmic translation and ribosome biogenesis. Cross-species comparison with human schizophrenia hippocampus revealed limited but directionally consistent gene-level overlap, with 21 of 23 shared differentially expressed genes showing concordant regulation. "Regulation of postsynaptic membrane potential" was the pathway significantly enriched across both species and analytical methods, encompassing both excitatory and inhibitory receptor subunits and synaptic regulators. Concordantly downregulated genes spanned glial markers and extracellular matrix components. These findings reveal a molecular signature of enhanced synaptic gene expression coupled with reduced translational capacity and glial support, with cross-species correspondence supporting the model's translational relevance and highlighting excitatory-inhibitory imbalance as a shared mechanism in hippocampal dysfunction underlying schizophrenia.
Repeated sleep deprivation selectively reactivates hippocampal CA1 pyramidal neurons.
Wang Y, Walsh EN, Kasuya J … +4 more , Remedies CE, Resch J, Lyons LC, Abel T
Mol Brain · 2026 Apr · PMID 41923141 · Full text
Sleep supports a variety of physiological processes, ranging from metabolic to immune system homeostasis, and plays a critical role in cognition and memory. A brief period of sleep loss impairs memory, particularly hippo...
Sleep supports a variety of physiological processes, ranging from metabolic to immune system homeostasis, and plays a critical role in cognition and memory. A brief period of sleep loss impairs memory, particularly hippocampus-dependent memories, alters molecular signaling, and synaptic plasticity in the hippocampus. Studies have shown that sleep deprivation (SD) alters neuronal activation as indicated by broad changes in gene expression signatures and by the increased expression of c-Fos, an immediate early gene that functions as a molecular marker of neuronal activity. In the present study, we examined hippocampal subregion-specific c-Fos induction patterns via immunohistochemical staining. We found that CA1 pyramidal neurons exhibit the most robust c-Fos induction after SD. Using an activity-driven ribosomal tagging system (c-Fos-RiboTag) and a repeated SD model, we labeled sleep deprivation activated CA1 neurons and observed a population of excitatory neurons in area CA1 that are reactivated by repeated SD. Using the c-Fos-RiboTag system that enables the isolation of ribosomes with attached mRNA from labeled neurons, we performed fosTRAP-seq and identified activity-dependent gene expression changes in c-Fos+ CA1 neurons. Our results revealed that synapse organization, protein dephosphorylation, cellular response to endogenous stimulus (such as insulin) are upregulated, whereas mRNA processing and splicing are downregulated. In summary, our study provides a detailed characterization of hippocampal neuronal activation following SD and identifies a subset of CA1 pyramidal neurons that are selectively reactivated by repeated SD. This SD-sensitive neuronal population enables investigation of molecular changes in neurons specifically impacted by sleep loss and suggests a potential connection between acute and chronic sleep loss at the cellular and molecular levels.
The neural code of perceptual inference.
Shin H
Mol Brain · 2026 Apr · PMID 41917990 · Full text
Perception is a process of inference, whereby incoming sensory evidence is interpreted based on prior expectations about the sensory world. Thus, the neural code of perception should be evaluated based on how optimally i...
Perception is a process of inference, whereby incoming sensory evidence is interpreted based on prior expectations about the sensory world. Thus, the neural code of perception should be evaluated based on how optimally it computes perceptual inference. However, the neural code of perception has conventionally been evaluated by its capacity to represent sensory information faithfully. Due to this misalignment in the computational goal of perception, assessments of the neural code have been biased towards discriminability over generalizability, and efficiency over robustness. In this review, I suggest ways in which we can evaluate the neural code based on its capacity to achieve the goal of perception, that is, perceptual inference.
APP family in inhibitory neurons controls inhibitory recruitment and short-term plasticity in the hippocampus.
Lee SH, Kang J, Zhang C … +2 more , Bolshakov VY, Shen J
Mol Brain · 2026 Mar · PMID 41906151 · Full text
Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer's disease. We previously reported that APP and its family members, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2...
Amyloid precursor protein (APP) is associated with both familial and sporadic forms of Alzheimer's disease. We previously reported that APP and its family members, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), regulate intrinsic neuronal excitability and synaptic plasticity in excitatory principal neurons, though APP family is dispensable for neuronal survival. However, the physiological role of APP family in inhibitory interneurons remains poorly understood. Here, we use our previously characterized floxed APP, APLP1, APLP2 and GAD2-Cre alleles to generate inhibitory neuron-specific conditional triple knockout (IN-APP/APLP1/APLP2 cTKO) mice. Our electrophysiological analysis of acute hippocampal slices revealed that IN-APP/APLP1/APLP2 cTKO CA1 pyramidal neurons exhibit increased amplitudes of evoked GABA receptor-mediated inhibitory postsynaptic currents (IPSCs), while basal spontaneous IPSC frequency and amplitude remain unchanged. At Schaffer collateral (SC)-CA1 synapses, short-train frequency facilitation is enhanced in slices from IN-APP/APLP1/APLP2 cTKO mice, whereas paired-pulse facilitation (PPF) and long-term potentiation (LTP) are normal. Consistent with a cell-autonomous interneuron defect, basal excitatory transmission, measured by spontaneous and miniature excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons, is unaltered. These data show that APP family in inhibitory interneurons regulates activity-dependent inhibitory output without overtly perturbing baseline glutamatergic transmission and thus, indirectly shapes short-term facilitation at SC-CA1 synapses. Together with our earlier findings in excitatory neuron-specific APP/APLP1/APLP2 cTKO mice showing intrinsic hyperexcitability, enhanced short-term facilitation, and impaired LTP, these results suggest that the APP family modulates inhibitory and excitatory functions at SC-CA1 synapses through complementary mechanisms in principal neurons and interneurons.
m6A RNA methylation in neural plasticity, brain aging, and neurodegenerative vulnerability.
Zhou X, Yu P, Shen X
Mol Brain · 2026 Mar · PMID 41906147 · Full text
m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its...
m6A is a pervasive post-transcriptional RNA modification that regulates RNA splicing, stability, localization, and translation in the brain. In this review, we outline the core m6A regulatory machinery and summarize its spatial organization across neurons and glial cells, highlighting established roles in brain development, synapse formation, and axon growth. We then focus on experience-dependent plasticity, synthesizing evidence that neuronal activity and environmental inputs dynamically reshape m6A to regulate immediate-early transcription and local translation at synapses across sensory, cognitive, emotional, and motor domains. With aging, m6A programs are reconfigured in a cell-type-specific manner, a shift associated with reduced plasticity and increased vulnerability. We further survey disease-associated alterations in m6A across Alzheimer's disease, Parkinson's disease, Huntington's disease, stroke-related cognitive impairment, ALS and FTD, as well as metal or toxin exposure, emphasizing convergent effects on dopaminergic and glutamatergic signaling, synaptic integrity, inflammation, and cellular stress responses. Finally, we discuss emerging opportunities and conceptual challenges in targeting m6A enzymes or reader proteins, and outline priorities for future work, including cell-type- and subcellular-resolved mapping, causal perturbation in defined circuits and life stages, and the development of biomarkers and selective modulators. Together, these observations position m6A as a molecular interface linking experience-dependent plasticity, brain aging, and neurodegenerative vulnerability.
Platelet proteomic signatures of amyloid β-positive mild cognitive impairment and Alzheimer's disease.
Cho YE, Kim A, Lee HM … +7 more , Oh JW, Son SJ, Roh HW, Jung YS, Hong CH, Lee SY, Kim KP
Mol Brain · 2026 Mar · PMID 41904574 · Full text
Early detection of Alzheimer's disease (AD) is critical for preventing disease progression. Blood platelets have emerged as a useful peripheral source for AD diagnosis. However, the identification of proteomics-based pla...
Early detection of Alzheimer's disease (AD) is critical for preventing disease progression. Blood platelets have emerged as a useful peripheral source for AD diagnosis. However, the identification of proteomics-based platelet biomarkers of mild cognitive impairment (MCI) and AD in relation to amyloid β (Aβ) deposition remains largely unexplored. In this study, we compared four groups from 18 participants: subjective memory impairment (SMI, n = 4) as cognitive normal controls, MCI without Aβ deposition (MCI-A(+), n = 5), MCI with Aβ deposition (MCI-A(-), n = 5), and AD (n = 4). We conducted in-depth platelet protein profiling using high-throughput LC-MS/MS with tandem mass tag labeling. Among the total 4,524 proteins detected, we identified both unique and overlapping differentially expressed proteins in MCI-A(+), MCI-A(-), and AD compared with SMI. Hierarchical clustering analysis revealed seven distinct patterns of proteomic alterations across groups. Functional network and gene ontology enrichment analyses indicated that each cluster was associated with specific processes, including platelet activation, AD, and apoptotic signaling pathways. Notably, upregulated proteins in MCI-A(-) and AD were linked to endomembrane system organization. Furthermore, we quantified the relative abundance of multiple protein candidates that were significantly altered in MCI-A(-) and AD compared with SMI and MCI-A(+). Our findings highlight several platelet proteins-ATP6V0C, AP4B1, RAB2B, PSMD9, FKBP1B, and mTOR-as potential molecular targets for predicting AD at the stage of MCI with Aβ deposition, providing new insights into amyloid-related neurodegeneration.
Central nervous system pericytes express soluble ST2 in inflammation and injury.
Jansson D, Highet B, Li S … +9 more , Stevenson TJ, Smyth LCD, Rustenhoven J, Feng S, Daneman R, Dorrier C, Clarkson A, Scotter E, Dragunow M
Mol Brain · 2026 Mar · PMID 41857656 · Full text
Brain pericytes are mediators of neuroinflammation, as evidenced in vitro, in animal models and humans. We and others have identified the platelet-derived growth factor (PDGF)-BB -PDGF receptor beta (PDGFRB) pathway as a...
Brain pericytes are mediators of neuroinflammation, as evidenced in vitro, in animal models and humans. We and others have identified the platelet-derived growth factor (PDGF)-BB -PDGF receptor beta (PDGFRB) pathway as a key modulator of inflammatory cues in human brain pericytes. We investigate the receptor for interkeukin-33 (IL-33), interkeukin-1 receptor-like 1 (IL1RL1; also known as ST2) as a highly upregulated transcript in response to PDGF-BB stimulation in pericyte cultures. We show that pericytes express transcripts for both the membrane bound form of the receptor (ST2L) and the soluble form (sST2) that acts as a decoy and blocks IL-33 signalling. Human brain pericytes secrete sST2 in response to PDGF-BB, but also to transforming growth factor alpha (TGF) alpha and interleukin-4 (IL-4), although they are unresponsive to IL-33 treatment. We also examine pericyte expression of both IL1RL1 transcripts using RNAscope in two different in vivo models of neuroinflammation, experimental autoimmune encephalitis (EAE) and photothrombotic stroke. We present data showing that in rodents pericytes increase transcript expression predominantly for soluble IL1RL1 in inflammatory and stroke models. Our results highlight a novel expression pattern of the soluble and membrane bound forms of the IL-33 receptor in vitro and in combination with our observations in vivo suggest that cerebrovascular pericytes may negatively regulate IL-33 signalling following injury or inflammatory insults to the brain.
Neuro-immune interactions underlying autoimmune diseases: insights from brain imaging data.
Gu J, Xing Z, Wang J … +7 more , He Y, Li J, Wu C, Kuo W, Yan X, Lin W, Chen T
Mol Brain · 2026 Mar · PMID 41857630 · Full text
Autoimmune diseases (AIDs) result from intricate interactions among genetic, environmental and immune factors, with emerging evidence underscoring the role of the central nervous system (CNS) in their pathogenesis. In th...
Autoimmune diseases (AIDs) result from intricate interactions among genetic, environmental and immune factors, with emerging evidence underscoring the role of the central nervous system (CNS) in their pathogenesis. In this study, we utilized two-sample Mendelian randomization to systematically explore the causal relationships between 3,935 brain imaging-derived phenotypes (IDPs) and eight AIDs, including atopic dermatitis, inflammatory bowel disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatoid arthritis and type 1 diabetes. We identified nine IDPs with causal associations to eight representative AIDs. Mediation analysis uncovered eight potential immune cells or inflammatory factors bridging IDPs and AIDs. These findings provide compelling evidence for the CNS's involvement in autoimmune progresses through neuro-immune pathways and underscore potential diagnostic and therapeutic targets within the neuro-immune axis. This study introduces a novel framework for investigating interdisciplinary interventions that target CNS-immune interactions in the context of AIDs.
Whole-brain efferent projections of glutamatergic neurons in the cingulate cortex of mice.
Shi F, Lei L, Qiu J … +3 more , Zhu Y, Wu H, Wu X
Mol Brain · 2026 Mar · PMID 41840687 · Full text
The cingulate cortex, on the medial cerebral hemisphere, is involved in cognitive processing, emotional regulation, nociception, voluntary motor control, and sleep modulation. Anatomically, the cingulate cortex is organi...
The cingulate cortex, on the medial cerebral hemisphere, is involved in cognitive processing, emotional regulation, nociception, voluntary motor control, and sleep modulation. Anatomically, the cingulate cortex is organized into three distinct subdivisions: anterior cingulate cortex (ACC, A24a/A24b), midcingulate cortex (MCC, A24a'/A24b'), and posterior cingulate cortex (PCC, A30/A29c). Although emerging evidence from rodent models has mapped cingulate cortical projections, a comprehensive characterization of whole-brain efferent pathways from glutamatergic neurons in adult mice remains incomplete. In the present investigation, we applied a homologous nomenclature system and utilized viral anterograde tracing techniques, integrating both coronal and sagittal fluorescence imaging modalities, to systematically map and reconstruct the comprehensive efferent projections of glutamatergic neurons in the ACC, MCC, and PCC of adult mice. The findings revealed that the ACC, MCC, and PCC share a conserved projection architecture with direct efferent connections to key brain regions such as the intra-cingulate cortex, cerebral cortex, subcortical telencephalon, thalamus, and brainstem. Furthermore, our analysis revealed significant heterogeneity in the spatial distribution of efferent projections among cingulate subregions. Each subregion of the cingulate cortex exhibited distinct neuroanatomical connectivity patterns, which were posited to mediate their specialized functional roles. Neuroanatomical findings provided a fundamental basis for subsequent investigations into the functional roles of glutamatergic neurons in the cingulate cortex. Moreover, these findings provided a detailed structural framework that facilitated the elucidation of neural mechanisms underlying specific physiological processes.
Unaltered empathy-related behaviors in Williams-Beuren syndrome mouse models.
So D, Cha HL, Lee S … +3 more , Kim S, Yoo E, Keum S
Mol Brain · 2026 Mar · PMID 41814397 · Full text
Williams-Beuren Syndrome (WBS), a neurodevelopmental disorder caused by a heterozygous microdeletion at chromosome 7q11.23, is characterized by hypersociability and enhanced affective empathy. However, the specific genet...
Williams-Beuren Syndrome (WBS), a neurodevelopmental disorder caused by a heterozygous microdeletion at chromosome 7q11.23, is characterized by hypersociability and enhanced affective empathy. However, the specific genetic and neural mechanisms within the WBS locus underlying this elevated empathic response remain unknown. Here, we investigated empathy-related behaviors, including observational fear and allogrooming, in WBS mouse models harboring a deletion within the conserved syntenic region on mouse chromosome 5. We demonstrate that WBS mice exhibited emotional contagion and prosocial consolation behaviors comparable to their wild-type controls. Furthermore, WBS mice with single-gene deletions of the cortex-enriched genes Abhd11, Limk1, Mlxipl, and Stx1a also showed unaffected empathic freezing behavior. Collectively, our findings suggest that the enhanced empathic responsiveness reported in individuals with WBS may be influenced by reduced social inhibition toward others, while acknowledging that limitations of current rodent behavioral assays preclude definitive conclusions regarding primary neural mechanisms of empathy.
PKMζ-KIBRA interactions, molecular turnover, and memory.
Hsieh C, Cano DA, Tsokas P … +4 more , Cottrell JE, Fenton AA, Shouval H, Sacktor TC
Mol Brain · 2026 Mar · PMID 41814337 · Full text
How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and...
How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory lasting at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continuously incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used AlphaFold 3 to predict the structures of KIBRA-PKMζ heterodimers and heterohexamers and to examine the sites of action of two different inhibitors of KIBRA-PKMζ interaction that disrupt established late-LTP and long-term memory. The structures predict that the peptide K-ZAP blocks formation of heterodimers, whereas the small molecule ζ-stat prevents PKMζ of one heterodimer from binding a second KIBRA and PKMζ, essential for forming larger oligomeric structures. We show that ζ-stat, like K-ZAP, disrupts 1-month-old spatial memory. Thus, continuous formation of KIBRA-PKMζ oligomers can be a core molecular mechanism driving the persistence of long-term memory in the face of molecular turnover.
Shank3B deficiency disrupts GABAergic synaptic transmission in pyramidal neurons of the medial prefrontal cortex region in autism spectrum disorder.
Yin H, Sun K, Wang C … +7 more , Fan S, Wang J, He S, Lei HM, Pang S, Chen J, Zhang G
Mol Brain · 2026 Mar · PMID 41803903 · Full text
Mutations in the SHANK3B gene have been strongly implicated in the pathogenesis of autism spectrum disorder (ASD). The medial prefrontal cortex (mPFC) is integral to emotional processing and social behavior, and its atyp...
Mutations in the SHANK3B gene have been strongly implicated in the pathogenesis of autism spectrum disorder (ASD). The medial prefrontal cortex (mPFC) is integral to emotional processing and social behavior, and its atypical development is closely associated with ASD pathogenesis. However, the electrophysiological characteristics of pyramidal neurons within the mPFC and the mechanisms of their synaptic transmission remain inadequately characterized. In the present study, we conducted whole-cell patch-clamp recordings on mPFC pyramidal neurons in Shank3b knockout mice. We observed significant alterations in the membrane properties and excitability of mPFC pyramidal neurons in Shank3b knockout mice; these were accompanied by reduced inhibitory postsynaptic currents and deficiencies in γ-aminobutyric acid (GABA) release or GABA receptor transport. Additionally, RNA sequencing analysis of PFC tissue revealed differentially expressed genes in Shank3b knockout mice compared with WT mice, with these genes enriched in synaptic function and calcium channel signaling pathways. These findings are consistent with our ultrastructural observations of a reduced postsynaptic density at excitatory synapses, which may further contribute to the impaired number and morphology of pyramidal neurons in the mPFC. Our research offers new insights into the disruption of PFC circuitry that is caused by Shank3b deficiency and establishes connections between the pathophysiological mechanisms underlying ASD and synaptic structural anomalies, ion channel dysregulation, and excitatory/inhibitory imbalances. Together, these findings highlight the importance of Shank3b-mediated regulation of GABA signaling and modulation of intrinsic excitability as prospective therapeutic targets for ASD.
Artificial intelligence-based biomarkers for the diagnosis and treatment of neurological conditions: a narrative review.
Ben-Jaafar A, Sinha A, Nkrumah-Boateng PA … +6 more , Roy S, Sanker V, Mohamed S, Sarfo-Adu F, Ali SH, Wireko AA
Mol Brain · 2026 Mar · PMID 41794848 · Full text
Artificial intelligence (AI) is transforming biomarker discovery in neurology by overcoming key limitations of conventional approaches that are often slow, reductionist, and unable to integrate complex multimodal data. I...
Artificial intelligence (AI) is transforming biomarker discovery in neurology by overcoming key limitations of conventional approaches that are often slow, reductionist, and unable to integrate complex multimodal data. In this narrative review, we searched the data bases; PubMed, Scopus, IEEE Xplore, CINAHL, Embase and the Cochrane Library from inception to 2025 to evaluate how AI supports biomarker identification, diagnosis, prognostication, and treatment stratification across neurovascular, neurodegenerative, neuro-oncological and seizure disorders. Evidence demonstrates that AI-driven imaging and multi-omics biomarkers can detect disease earlier, improve prediction accuracy, and support personalised care. For example, AI models improve stroke outcome prediction beyond conventional scores, identify intracranial aneurysms with sensitivities exceeding 90%, predict conversion from mild cognitive impairment to Alzheimer's disease with accuracies approaching 85-90%, and extract radiogenomic biomarkers in gliomas that outperform traditional diagnostic strategies. However, real-world translation remains constrained by dataset bias, limited external validation, interpretability challenges, and gaps in generalisability, particularly in underrepresented populations. Overall, AI-driven biomarker discovery offers a powerful pathway toward precision neurology, with the greatest impact expected when technical innovation is paired with robust clinical validation, regulatory integration, and equitable data representation.
Upregulation of TRPV2 exacerbates age-related hearing loss by promoting oxidative stress in spiral ganglion neurons.
Zhang Z, Yin H, Cao H … +9 more , An M, Li Y, Yang J, Liu T, Wang J, Zhao L, Wang C, Miao R, Wang B
Mol Brain · 2026 Mar · PMID 41792750 · Full text
Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver o...
Age-related hearing loss (ARHL) is a prevalent neurodegenerative condition characterized by the progressive loss of spiral ganglion neurons (SGNs). Although oxidative stress is recognized as a central pathogenic driver of ARHL, the precise molecular triggers that initiate and amplify SGN damage remain elusive. Here, we investigated the role of the Transient Receptor Potential Vanilloid 2 (TRPV2) channel in ARHL. We found that TRPV2 expression was significantly upregulated in the SGNs of aged mice, which was associated with elevated oxidative stress. Pharmacological activation of TRPV2 in 6-month-old mice (a pre-senescent stage with preserved baseline hearing) accelerated the onset of high-frequency hearing damage, as evidenced by auditory brainstem response (ABR) measurements. Consistently, TRPV2 activation exacerbated oxidative damage (assessed by 4-HNE staining) and increased apoptotic cell death (detected via TUNEL) in the SGN population. In primary SGN cultures, TRPV2 overexpression aggravated oxidative stress, whereas TRPV2 knockdown in SH-SY5Y cells (a human neuroblastoma cell line) markedly mitigated the oxidative injury as reflected by reduced 4-HNE. Our findings establish that the age-related upregulation of TRPV2 sensitizes SGNs to oxidative stress, thereby promoting neuronal damage and exacerbating ARHL. This work highlights TRPV2 as a promising therapeutic target for intervening in the progression of ARHL.
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